Publication

Function and regulation of AUTS2, a gene implicated in autism and human evolution.

Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.

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A central public database of experimentally validated human and mouse noncoding fragments with gene enhancer activity as assessed in transgenic mice. Most of these noncoding elements were selected for testing based on their extreme conservation with other vertebrates or epigenomic evidence (ChIP-Seq) of putative enhancer marks. For each positive enhancer, digital images of whole-mount embryo staining at embryonic day 11.5 are provided and an anatomical description of the reporter gene expression pattern. Users can retrieve elements near single genes of interest, search for enhancers that target reporter gene expression to a particular tissue, or download entire collections of enhancers with a defined tissue specificity or conservation depth. External groups are invited to submit computational predictions of developmental enhancers, as they have resources to test a limited number of such elements in their transgenic assay. As of 3/11/2014 the database contains information on 2121 in vivo tested elements - 1126 elements with enhancer activity. LacZ reporter vectors for most constructs, as well as archived (PFA-stored) transgenic embryos for selected elements can be made available to outside investigators upon request. Please inquire at Enhancer Support, enhancer.support (at) gmail.com

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